1. Field of the Invention
The invention relates to a method of identifying and treating patients having early, recently diagnosed noninsulin-dependent diabetes and to compositions useful in the treatment of such diabetics. In particular, the method involves the use of compositions that effectively raise plasma cholecystokinin levels thereby alleviating rapid gastric emptying and restoring various glucose metabolic indicators to normal or near-normal levels.
2. Description of Related Art
In recent years the role of the stomach in glucose homeostasis has become recognized. In 1982, Thompson, et al. described gastric emptying as an important determinant of the oral glucose tolerance test and suggested that the glucose tolerance test could be used to assess gastric emptying. In 1983 Brener et al. described characteristic gastric emptying of glucose solutions in normal human subjects. Those studies showed that glucose empties from the stomach in a constant and linear fashion at an average of 2.13 kcal/min regardless of the concentration of the glucose solution. Prior to this study, it was widely believed that all liquids emptied in an exponential manner. It is Brener's hypothesis that a dynamic "closed loop" feedback interrelationship exists between the stomach and the duodenum to control the delivery of calories from the stomach.
Keshavarzian et al. (1987) have studied gastric emptying in a heterogeneous group of diabetics with insulin-dependent diabetes mellitus and non-insulin dependent diabetes mellitus who had been diagnosed with the disease for more than 5 years. Although Keshavarzian emphasized the delay in gastric emptying, particularly with solids, some diabetic subjects in the study exhibited a more rapid gastric emptying compared to controls. Liquid gastric emptying was generally the same for both the controls and diabetics with the gastric half-emptying time (t1/2) showing no significant difference. It was noted that some of the patients exhibited abnormally fast emptying of liquids, but Keshavarzian, et al. attached no significance to the observation.
Campbell et al. (1977) described delayed gastric emptying in 10 of 12 diabetic subjects. Although the majority of the patients showed delayed gastric emptying, two of the subjects exhibited more rapid gastric emptying rates compared with controls.
Horowitz et al. (1989) described delayed gastric and esophageal emptying in 20 subjects with non-insulin dependent diabetes mellitus. The duration of known diabetes in the subjects ranged from 1-20 years. Although two of the subjects exhibited more rapid than normal liquid gastric emptying, the group of 20 as a whole exhibited delayed liquid gastric emptying (t1/2) slower than in normal patients, p&lt;0.05). There was significant delay of solid food emptying in these patients (increased retention of solid food at 100 min, p&lt;0.001).
Gastric emptying has been studied as a non-invasive diagnostic tool as an indicator of metabolic and neural disturbances. For example, chronic forms of gastric stasis can be caused by innervation abnormalities in diabetics with autonomic neuropathy (Smout, 1986). Many other conditions have been studied, including those in patients who had stomach operations or diseases of the gastrointestinal tract. Generally, the majority had delayed gastric emptying (Pellegrini, et al., 1983). In particular, delayed gastric-emptying appears to be a phenomenon associated with diabetes.
Methods of regulating pyloric functions are known in the art. Diabetic gastroparesis and hypertrophic pyloric stenosis are examples of conditions successfully treated (Akkermans, et al., 1989); delayed gastric emptying has been treated with drugs that accelerate the emptying process; for example, metoclopramide or domperidone. An opposite effect is shown by Propantheline and opiates which delay gastric emptying (Chaudhuri, et al., 1990).
There is some information on the effects of different compounds on enzyme components of pancreatic secretion, for example, the role of cholecystokinin (CCK) (Liddle, et al., 1988) and possible regulatory control by other gut hormones, such as VIP which stimulate insulin release from the pancreas (Schwartz, et al., 1990). It is known that CCK has a significant role in regulating glucose homeostasis in humans (Liddle, et al., 1988) and that it delays gastric emptying and reduces hyperglycemia (Jenkins, et al., 1990). However, the connection between CCK secretion on gastric emptying and insulin release in normal and diabetic patients has not yet been fully evaluated (Liddle, 1990).
Studies so far reported indicate that in diabetic patients, delayed gastric emptying is typical. However, until now, there was no realization that certain classes of patients, those not yet manifesting overt diabetes, those at risk to develop diabetes, those in early stages of diabetes and many patients having non-insulin dependent diabetes, exhibit abnormally rapid gastric emptying. It was this unexpected and surprising discovery that led to the development of a method of a simple treatment. By delaying gastric emptying in this group of patients at high risk to develop diabetes, or in those with recent onset of diabetes, insulin and plasma glucose levels after a meal may be maintained at levels much closer to normal nondiabetic levels. This allows a delay of nutrient absorption which has been recognized to result in increased economy of glucose disposal and insulin economy (Jenkins, et al., 1990). This is a first and significant step in early treatment of those at risk for developing debilitating forms of diabetes, even insulin-dependent diabetes, and may delay or forestall completely the usual progress of the disease.